The overall goal of this project is to identify genetic risk factors for childhood-onset affective disorders. Genetic factors are strongly implicated in the etiology of affective disorder by numerous family, twin and adoption studies. By studying childhood- onset depression (COD) we will be able to access a more rare, more familial, and therefore less heterogeneous form of affective disorder. We plan to identify genes that contribute to the development of COD using a strategy that combines affected relative pairs (ARP) and association studies that employ family based controls which we call haplotype relative risk (HRR) methods. The research plan is to collect DNA from childhood-onset unipolar depression probands, their parents, and their affected relatives. Our ultimate goal for the five year study is to collect 200 COD probands and 200 affected relatives of these probands for the affected relative pair study and 100 pairs of parents of the probands for the HRR study. With 153 unipolar probands, 163 affected relatives, and 85 sets of parents already identified we are well poised to achieve this goal. DNA will be extracted from blood or buccal mucosa taken from these probands, affected relatives, parents and when available, from connecting family members in the pedigree. We will type the DNAs from the ARP sample and the HRR sample for evaluation of candidate genes. We have chosen candidate genes that have been implicated by biological studies of depressives. These include genes from the neurotransmitter systems (serotonergic, noradrenergic, cholinergic, and dopaminergic) and from the hypothalamic-pituitary-adrenal axis. In addition, we will screen the probands and parents for the presence of expanded trinucleotide repeats as some evidence for genetic anticipation has been documented for affective disorders. We will also perform a genome scan of all chromosomes using the ARP sample with evenly spaced, highly informative markers. The finding of an increased sharing of alleles in affected relatives at a DNA marker will indicate the position of an affective disorder susceptibility gene.